1. Field of the Invention
The present invention relates to novel modified polymers having superior blood compatibility produced by substituting polymeric substrates having active sites of amide or acid amide groups, such as polyurethane, polyamide and polyacrylamide, with sulfonated polyethyleneoxide PEO--SO.sub.3 H, and a process for the preparation of the same modified polymers.
It has been found from the results of in vitro and ex vivo tests that the modified polymers of the invention show attributing to the synergistic effects of the exclusion of the proteins and platelets by the hydrophilic polyethyleneoxide polymers and the antithrombogenic action of the sulfonate anions when the modified polymers are in contact with blood.
The modified polymers according to the invention are useful especially as a variety of medical materials such as materials of the artificial organs for the circulatory system in contact with blood, e.g., artificial hearts, artificial blood vessels, artificial heart valves, artificial blood oxygenaters, artificial kidneys, etc. The modified polymers also are useful as construction and coating materials of the medical devices and instruments to be inserted into blood vessels such as vein catheters, intra-aortic balloon pumps, and artery catheters. When using the modified polymers of the inventions, the polymers can decrease significantly the thrombogenic action (thrombus) and, thus, prevent well undesirable side effects of the blood vessel occlusion.
The modified polymers of the invention can be prepared by introducing a PEO derivative having functional groups capable of reacting with the active sites of a polymeric into said polymeric substrate, and then reacting the substrate with a suitable sulfonic acid derivative, or by directly reacting the substrate with a PEO derivative having both functional groups capable of reacting with the active sites and a sulfonate group in a single pot step. Where the PEO derivative reacts with the above polymeric substrate, at the sites of the free monofunctional group introduced by the reaction of the substrate with diisocyanate or diacid chlorides, the reaction may proceed well under mild conditions.
Useful PEO derivatives may include PEO and its amines, p-toluenesulfonic ester, acid chlorides, isocyanates, epoxy, or halogen derivatives, etc. The sulfonate derivatives capable of reacting with PEO derivatives may include sulfites and their salts, bisulfites and their salts, aminoalkylsulfonic acid, hydroxyalkylsulfonic acid, and alkylsultone, etc. These sulfonate derivatives can be selected depending upon the nature of the functional groups of the PEO derivative introduced.
Medical materials require outstanding physical and mechanical characteristics, stability in vivo, sterilizability, and biocompatibility. Among these characteristics, biocompatibility is the most critical factor, supressing the rejection symptoms apt to naturally occur when the materials are brought into contact with human body tissues and/or blood.
When the blood vessel is destroyed or when blood is in contact with a foreign substance, the thrombus is generated due to the blood clotting.
Although the mechanism of the thrombus (blood clotting) has not yet been known in detail, it may be summarized as shown in the following diagram. ##STR1##
As shown in the above diagram, it is understood that the thrombus starts with the adsorption and activation of the blood proteins and platelets, followed by the activation of the coagulation factor. The thrombus ends in the formation of a network-structured fibrins in the presence of erythrocytes and leukocytes.
The thrombus may and can cause fatal problems like the blood vessel occlusion due to emboli when using certain materials as construction materials for internal circulatory system organs such as artificial hearts, artificial blood vessels, artificial kidneys and artificial blood oxygenaters, or other medical devices and/or instruments to be inserted into the blood vessels. Accordingly, the development of a material having superior blood compatibility or antithrombogenicity, capable of supressing the thrombus in contact with blood has hitherto been desired strongly.
2. Description of the Prior Art
In general, polymeric materials with blood compatibility which have hitherto been studied can be classified into two classes. One is the material supressing the adsorption and activation of the blood components, inter alia, proteins and platelets, as the material naturally having blood compatibility. Pseudointima-forming materials have also been studied, utilizing blood compatibility of a pseudointramembrane formed on the surface of the materials. The other is the material wherein physiologically active materials such as heparin, prostaglandin, and urokinase, which suppress thrombus are immobilized or slowly released onto the surface of the substrate to obtain desired blood compatibility.
Artificial blood vessels manufactured of polyester fabrics or expanded tetrofluoroethylene fluorocarbon polymer initially cause thrombus occurred on the surface thereof in contact with blood. The clotting layer resulted from the thrombus is the so-called pseudointima which has blood compatibility. These materials are hardly applied to the blood vessels in a small diameter or the blood vessels having a slow blood flow rate. Catheters using a physiologically active material such as heparin and development of the material were reported by Y. Mori et al., in Trans. ASAIO, 24: 736-745, (1978). However, there are found many limitations and inferiority in their effects due to the loss of physiologically active materials and the decrease of their activity.
Accordingly, a number of studies have been made to develop the materials having essentially superior blood compatibility.
Blood compatibility of a material is determined depending on the physiochemical structure of its surface, and significantly affected by its polarity, surface energy, surface electrical charge, hydrophilicity and hydrophobicity, the surface smoothness and porosity, and the like.
Surface free energy of a material is one of the important factors for determination of the blood compatibility. Hydrogels containing a lot of water are known as the materials having good blood compatibility since they exhibit a very low interfacial energy at the time of the interaction with blood. However, since those hydrogels have poor processing properties and mechanical strength, studies for the methods of grafting or coating on the substrate surface have been made.
Particularly, a number of studies have been made of PEO, a hydrophilic polymer. An antithromobogenic material was reported, which is prepared by grafting PEO on the surface of a polyvinyl chloride resin (Nagaoka et al., Trans. ASAIO 28: 459-463, (1982)). They emphasized in the report that the adhesion of the proteins and plaletets in the blood components could be suppressed by the excluded volume effect and the dynamic movement of hydrophilic PEO polymer chains grafted on its surface.
On the other hand, it has been reported that a polymer having a micro domain hydrophilic/hydrophobic structure can supress the activation of the proteins and platelets in the blood components and, thus, results in good antithrombogenic properties.
T. Okano et al. reported that a polystyrene-polyhydroxy ethylmethacrylate block copolymer has good antithrombogenic properties [T. Okano et al., J. Biomed. Mater. Res.,15: 393-402 (1981)].
In addition, polyurethane polymerized from a polyol/diisocyanate shows relatively antithrombogenic properties owing to its hydrophilic/hydrophobic structure [M. D. Lelah et al., J. Biomed. Mater. Res.,20: 433-468, (1986)]. Particularly, the polyurethane has outstanding mechanical characteristics. Therefore, it is now widely used as a material for constructing medical devices and instruments such as artificial hearts, intra-aortic balloon pumps, and blood vessel catheters to be in contact with blood.
On the other hand, it has been reported that blood components and blood vessel endothelial cells are negatively charged and, therefore, supression of the clotting in the blood vessels is owing to the electrical repulsion between the components and the cells [P. N. Sawyer et al., Amer. J. Physiol.,175:113, (1953)]. Accordingly, the polymer surface containing anions also exhibits good blood compatibility. For example, it has been reported, by F. J. Walker et al., in Biochem. Biophys. Res. Commu.,93:1339 (1987), that the unique suppression action of the thrombus by heparin, a linear anionic carbohydrate, is ascribed to the anions involved, such as sulfonate and aminosulfonate groups. This type of an anionic polymer includes sulfonated polystyrene [C. Fougnot et al. in Ann Biomed. Eng.,7: 429-439, (1979)]. According to another report, it is noted that the sulfonated polyurethane can improve considerably blood compatibility [S. L. Cooper et al., J. Colloid Interface Sci.,104: 422-439, (1985)].